The long-range goal is to understand how animals process and remember events and develop a neurochemically guided theoretical framework to understand memory disorders. Because the apolipoprotein E ?4 allele (APOE4) confers a high risk of Alzheimer's disease (AD), we will use knockin rats that have received homozygous replacement of the rat apolipoprotein E (APOE) gene with the human APOE4 gene. The objective of this exploratory R21 application is to assess the impact of human APOE4 on episodic memory in an animal model of cognitive decline in aging. The central hypothesis is that humanized APOE4 gene insertion impairs episodic memory in old age. Our preliminary studies, using a related knockout rat model, show that deletion of the rat APOE gene protects spatial working memory (while controlling for spatial perception, learning, motivation, motor control, and other non-specific factors). We will test age-related cognitive decline in APOE4 knockin and wildtype rats using models which document that rats use episodic memory to (1) answer an unexpected question after incidental encoding of information (unexpected-question approach) and (2) remember multiple items and the context in which the items occurred (items-in-context approach). The PI will test the central hypothesis by accomplishing two specific aims: (1) To identify the impact of human APOE4 insertion on age-related cognitive decline in episodic memory using our unexpected-question approach. We will use our unexpected-questions approach to quantify episodic memory in humanized APOE4 knockin (KI) and wildtype (WT) rats at young and old timepoints in a longitudinal design. (2) To identify the impact of human APOE4 insertion on age-related decline in episodic memory using our items-in- context approach. We will use our items-in-context approach to quantify episodic memory in humanized APOE4 KI and WT rats at young and old timepoints in a longitudinal design. In each aim, we will measure A?, APOE4 expression, and cell death to estimate the correlation with episodic memory performance, and we will test the working hypothesis that human APOE4 insertion promotes cognitive decline in aged rats. We will use humanized APOE4 KI rats to manipulate the biological mechanisms that are responsible for episodic memory impairments in AD. Health relatedness of the project: Episodic memory is impaired in AD and normal aging. APOE4 is postulated to be responsible for episodic memory impairments in AD. Because the loss of episodic memory is the most debilitating cognitive impairment in AD, development of preclinical models of episodic memory is critical for improving translation of preclinical research. Improving memory is an important objective for therapies of AD and age-related cognitive decline. The development of an animal model of episodic memory impairment in AD may ultimately be used to (1) elucidate the mechanisms in AD pathogenesis and in normal aging and (2) enable future research to perform preclinical validations of novel therapeutics using pharmacological, molecular, and genetic techniques to treat cognitive decline in AD and aging.